The invention relates generally to detecting diseases of the urinary tract, and more particularly, relates to reagents such as polynucleotide sequences and the polypeptide sequences encoded thereby, as well as methods which utilize these sequences, which reagents are useful for detecting, diagnosing, staging, monitoring, prognosticating, in vivo imaging, preventing or treating, or determining predisposition to diseases or conditions of the urinary tract such as urinary tract cancers.
The organs of the urinary tract include the bladder, kidneys, and ureter. The incidence of urinary tract cancers in the United States is projected to be 86,300 cases diagnosed and 24,700 related deaths to occur during 1998. The most prevalent of the urinary tract cancers is bladder cancer, with projections of 54,400 new cases diagnosed and 12,500 related deaths to occur during 1998 (American Cancer Society statistics).
Procedures used for detecting, diagnosing, staging, monitoring, prognosticating, in vivo imaging, preventing or treating, or determining predisposition to diseases or conditions of the urinary tract such as urinary tract cancers are of critical importance to the outcome of the patient. For example, patients diagnosed with localized bladder cancer have a greater than a 90% five-year survival rate as compared to a survival rate of 50%, and less than 10%, for patients diagnosed with regionally extended and distally metastasized bladder cancers, respectively (American Cancer Society statistics). Currently, the best initial indication of early bladder cancer is the presence of microscopic hematuria which, if detected, may lead to the invasive and costly procedures of cystoscopy and cytology, procedures that are necessary for a definitive diagnosis. Hematuria are eventually diagnosed with bladder cancer. Thus, use of hematuria as a marker for bladder cancer results in many unnecessary cystoscopic and cytological procedures. C. McNeil, J. National Cancer Institute 23, 1704-1705 (1996). In addition, 20% of bladder cancer cases are negative for hematuria. D. L. Lamm, et al., CA Cancer J. Clin. 46: 93-112 (1996).
Bladder cancer patients are closely monitored by cystoscopy to detect persistent or recurrent disease or to detect early distant metastasis because recurrence rates following initial treatment are high (50-80%). W. R. Fair, et al., In: Cancer: Principles and Practice of Oncology, Fourth Edition, pp. 1052-1072, Philadelphia, Pa.: J. B. Lippincott Co. 1993. This procedure is performed every three months for at least five years. C. McNeil, supra. In addition, cytology, another mainstay of bladder cancer monitoring, is unreliable in detecting superficial, grade 1 tumors. G. M. Farrow, J. Occupational Med. 32: 817-821 (1990). Alternative methods that are sensitive for detecting bladder cancer and/or its recurrence and which are less expensive and/or invasive, therefore, are needed.
A critical step in managing patients with urinary tract cancer is the presurgical staging of the cancer to provide prognostic value and criteria for designing optimal therapy. For example, clinical and pathological staging of bladder cancer can disagree in more than 50% of patients with respect to the extent of invasion by a primary tumor. W. R. Fair, supra. Therefore, clinical staging of urinary tract cancers could be improved by utilizing new markers found in serum or urine which could differentiate between different stages of muscle invasion. Such markers could be mRNA or protein markers expressed by cells originating from the primary tumor but residing in blood, bone marrow or lymph nodes, and could serve as sensitive indicators for metastasis to these distal organs. For example, bladder cells have been detected in the bone marrow of patients with bladder cancer using immunohistochemical techniques, thus suggesting the occurrence of metastasis to the bone. K. Pantel, et al., Onkologie 18: 394-401 (1995).
Such procedures also could include assays based upon the appearance of various disease markers in test samples such as blood, plasma, serum or urine obtained by minimally invasive procedures which are detectable by immunological methods. These procedures would provide information to aid the physician in managing the patient with disease of the urinary tract at a low cost to the patient. Markers such as prostate specific antigen (PSA) and human chorionic gonadotropin (hCG) exist and are used clinically for screening patients for prostate cancer and testicular cancer, respectively. For example, PSA normally is secreted by the prostate at high levels into the seminal fluid, but is present in very low levels in the blood of men with normal prostates. Elevated levels of PSA protein in serum are used in the early detection of prostate cancer or disease in asymptomatic men. See, for example, G. E. Hanks, et al., In: Cancer: Principles and Practice of Oncology, Vol. 1, Fourth Edition, pp. 1073-1113, Philadelphia, Pa.: J. B. Lippincott Co. 1993. M. K. Schwartz, et al., In: Cancer: Principles and Practice of Oncology, Vol. 1, Fourth Edition, pp. 531-542, Philadelphia, Pa.: J. B. Lippincott Co. 1993. Likewise, the management of urinary tract diseases could be improved by the use of new markers normally expressed in an organ of the urinary tract but found in elevated amounts in an inappropriate body compartment as a result of the disease of the urinary tract.
Further, new markers which could predict the biologic behavior of early urinary tract cancers would also be of significant value. Early urinary tract cancers that threaten or will threaten the life of the patient are more clinically important than those that do not or will not be a threat. G. E. Hanks, supra. A need therefore exists for new markers which can differentiate between the clinically important and unimportant urinary tract cancers. Such markers would allow the clinician to accurately identify and effectively treat early cancers localized to the urinary tract which could otherwise metastasize and kill the patient. For example, the detection by immunoassay of a protein marker appearing in urine prior to or concomitant with bladder cancer recurrence would be useful. NMP22 and BTA are two protein markers found in urine which currently are being evaluated for utility as monitoring markers. C. McNeil, supra. Preliminary results with these markers suggest that a different marker with greater sensitivity and/or specificity would provide further improvement for the accurate detection of bladder cancer.
It therefore would be advantageous to provide specific methods and reagents for the early detecting, diagnosing, staging, monitoring, prognosticating, in vivo imaging, preventing or treating, or determining predisposition to diseases and conditions associated with the urinary tract. Such methods would include assaying a test sample for products of a gene which are overexpressed in diseases and conditions associated with the urinary tract including cancer. Such methods may also include assaying a test sample for products of a gene which have been altered in the disease or condition associated with the urinary tract. Such methods may further include assaying a test sample for products of a gene whose distribution among the various tissues and compartments of the body have been altered by a urinary tract-associated disease or condition including cancer. Such methods would comprise making cDNA from mRNA in the test sample, amplifying, when necessary, portions of the cDNA corresponding to the gene or a fragment thereof, and detecting the cDNA product as an indication of the presence of the disease or condition including cancer, or detecting translation products of the mRNAs comprising gene sequences as an indication of the presence of the disease. Useful reagents include polynucleotide(s), or fragment(s) thereof which may be used in diagnostic methods such as reverse transcriptase-polymerase chain reaction (RT-PCR), PCR, or hybridization assays of mRNA extracted from biopsied tissue, blood or other test samples; proteins which are the translation products of such mRNAs; or antibodies directed against these proteins. Such assays would include methods for assaying a sample for product(s) of the gene and detecting the product(s) as an indication of disease of the urinary tract. Drug treatment or gene therapy for diseases and conditions of the urinary tract including cancer can be based on these identified gene sequences or their expressed proteins, and efficacy of any particular therapy can be monitored. Furthermore, it would be advantageous to have available alternative, non-surgical diagnostic methods capable of detecting early stage urinary tract disease such as cancer.